the opportunity to delineate the pathogenesis of its phenotype. Based on structural and functional similarities between plakoglobin (PG), a desmosomal protein and a member armadillo family, and -catenin, the signal transducer of the canonical Wnt signaling and also an armadillo protein, we posit competitive interactions between PG (aka -catenin) and -catenin suppresses the canonical Wnt signaling, leads to myocyte apoptosis and enhanced adipogenesis. To test the hypothesis, we generated cardiac-restricted desmoplakin (DP) deficient mice and siRNA-mediated DP-deficient atrial myocytes. We showed DP-deficiency led to nuclear translocation of PG, suppression of the canonical Wnt signaling, myocyte apoptosis, fibrosis and adipogenesis. We propose to identify the cellular origin of excess adipocytes in the heart, delineate the molecular basis of suppressed canonical Wnt signaling and prevent the phenotype by activating the canonical Wnt signaling. The aims are: 1. To identify the cellular origin of excess adipocytes in ARVC through in vivo genetic fate-mapping and co-culture studies; 2. To determine whether suppressed canonical Wnt signaling is a common mechanism for the pathogenesis of ARVC by expression of titratable levels of mutant desmosomal proteins in transgenic mice hearts; 3. To delineate the mechanism by which nuclear PG suppresses the canonical Wnt signaling by studying protein-protein interactions and the effects of PG on effective assembly of Wnt core proteins complex; 4. To rescue the ARVC phenotype in vivo and in vivo by activating the canonical Wnt signaling through conditional activation of degradation-resistant -catenin and pharmacological activation and hence, to fulfill the Koch's postulates of causality. Studies in genetically modified mice, transduced cardiac myocytes and myofibroblasts are designed to delineate the components of each aim. The results could elucidate the molecular pathogenesis of desmosomal ARVC and lead to identification of new molecular diagnostic markers and novel pharmacological targets for the treatment and prevention of ARVC in humans. Project Description Page 6